2007 ACC/AHA GUIDELINES FOR THE MANAGEMENT OF NSTE-ACS: OPTIMAL ANTICOAGULATION AND ANTIPLATELET THERAPY

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1 2007 ACC/AHA GUIDELINES FOR THE MANAGEMENT OF NSTE-ACS: OPTIMAL ANTICOAGULATION AND ANTIPLATELET THERAPY Charles V. Pollack, Jr., MA, MD, FACEP, FAAEM, FAHA Professor and Chairman, Department of Emergency Medicine Pennsylvania Hospital, University of Pennsylvania, Philadelphia, PA Objectives: 1. Relate the importance of balancing anti-ischemic efficacy with adverse bleeding potential when selecting anticoagulant and antiplatelet therapies for NSTE-ACS. 2. Discuss the demonstrated benefits of following evidence-based recommendations for the management of high-risk NSTE-ACS patients. 3. Elaborate on the importance of continuity of risk stratification and treatment decisions as patients with NSTE-ACS leave the ED and enter cardiology care. INTRODUCTION The 2002 American College of Cardiology (ACC) / American Heart Association (AHA) Guidelines for the Management of Non-ST-Segment-Elevation Acute Coronary Syndrome (NSTE-ACS) were updated in August 2007, 1 and provide for emergency physicians an evidencebased framework for the assessment, risk stratification, and initial risk-based management of patients with unstable angina and NSTE myocardial infarction (NSTEMI). Although this wideranging document addresses all aspects of upstream (that is, prior to diagnostic angiography) and post-cath care of this challenging population, this review will focus specifically on the recommendations for optimal anticoagulation and antiplatelet therapy. Anticoagulation Therapy Anticoagulation is appropriate for patients deemed to be at intermediate or higher ACS ischemic risk. There are many options for anticoagulation in the upstream environment, and the choice may be made according to (1) emergency physician preference, (2) cardiologist preference, (3) perceived level of ischemic risk, (4) concern for bleeding complications after initiation of therapy, (5) likely duration of upstream therapy, (6) logistical issues such as FDA labels and formulary inclusion, and (7) local standard of care. There are more options than ever for anticoagulation in the ACS patient, including both indirect antithrombin agents (unfractionated heparin, low-molecular-weight heparins, and anti-xa inhibitors) and direct antithrombin agents. Comparing these options headto-head is often problematic, as trials are often designed or executed in a fashion that makes uncertain (1) adjustments for equipotency of drugs being compared, (2) the impact of prerandomization anticoagulation therapy, often administered in the emergency department (ED), (3) the inconsistency and impact of concomitant antiplatelet therapy, (4) the intensity of procedures received by patients, (5) compliance with the study protocol In the ED, bleeding risk is difficult to quantify, but may be assumed to be higher than average in patients who are older, female, have diminished renal function, and are anemic at presentation. 1

2 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies ( especially in open-label studies), and (6) basic study design issues, such as superiority vs noninferiority endpoints. The 2007 Guidelines also place an increased emphasis on the avoidance of bleeding complications in the management of NSTE-ACS. 1 Because of growing concern over a possible relationship between bleeding events and increased risk of ischemic events and death, 2 there are new recommendations for drug therapy that inform choices among agents by associated bleeding risk. In the ED, bleeding risk is difficult to quantify, but may be assumed to be higher than average in patients who are older, female, have diminished renal function, and are anemic at presentation. 1,3 The major new studies of anticoagulants considered in the 2007 Guidelines are the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial, 4 the Organization to Assess Strategies for Ischaemic Syndromes (OASIS)-5 study, 5 and the Acute Catheterization and Urgent Intervention Tri age strategy (ACUITY) trial. 6 The dosing interval for enoxaparin should be doubled from 12 to 24 hours if creatinine clearance is less than 30cc/min. SYNERGY was a study that compared enoxaparin with UFH in patients with NSTE-ACS and highrisk features who were to be treated with an early invasive approach. The dose of enoxaparin was 1mg/kg subcutaneously (SC) every 12 hours, with a supplemental IV dose (0.3 mg/kg) given in the event of PCI more than eight (but less than 12) hours after the last SC dose. The dose of UFH was an IV bolus of 60 U/kg (up to 5000U), then an initial infusion of 12 U/kg/hr (up to 1000 U/hr), further adjusted with a goal activated partial thromboplastin time (aptt) of sec. Patients with an estimated creatinine clearance of less than 30 cc/min were excluded. Patients may have received no anticoagulation or treatment with either enoxaparin or UFH prior to randomization. All other treatment (clopidogrel, glycoprotein IIb/IIIa inhibitors (GPI), beta-blockers, statins, etc) was left to the discretion of the treating physician, although compliance with the 2002 Guidelines was encouraged. 4 Overall, 92% of the patients underwent diagnostic angiography, and roughly half of those underwent PCI; 19% of the 10,027 patients underwent CABG, a high proportion probably attributable to the advanced age of the subject population. There were no baseline or procedural intensity differences between the two groups. Median time from randomization to catheterization was 22 hours, although some 8-10 hours typically elapsed between presentation and randomization. The primary efficacy endpoint failed to show superiority of enoxaparin, although noninferiority criteria (at a 10% margin) were satisfied; 14.0% of the enoxaparin patients had death or MI by 30 days, while 14.5% of the UFH patients met the endpoint (hazard ratio, 0.96; 95% CI, 0.86, 1.06). The safety endpoint was less clear, with enoxaparin being associated with a statistically significant increase in TIMI major bleeding (9.1% vs 7.6%, p = 0.008) and nonsignificant excesses of GUSTO severe bleeding (2.7% vs 2.2%, p = 0.08) and red cell transfusions (17.0% vs 16.0%, p = 0.16). 4 At least some of the excess bleeding was attributable to crossover from enoxaparin to UFH at the time of PCI in this unblinded study, 7 once more reinforcing the need for good communication and collaboration between emergency physicians and cardiologists. The 2007 Guidelines give enoxaparin an I-A recommendation for use as an anticoagulant in NSTE-ACS. 1 The dosing interval for enoxaparin should be doubled from 12 to 24 hours if creatinine clearance is less than 30 cc/min. 2

3 2007 ACC/AHA GUIDELINES FOR THE MANAGEMENT OF NSTE-ACS: OPTIMAL ANTICOAGULATION AND ANTIPLATELET THERAPY The OASIS-5 study compared fondaparinux to enoxaparin in patients with NSTE-ACS and high-risk features. 5 Fondaparinux is an indirect (mediated via Antithrombin III, as with UFH and LWMHs) inhibitor of Factor Xa. Inhibition at the Xa step of the coagulation cascade blocks the amplification of downstream coagulation reactions and therefore impedes the generation of thrombin, although there is no action against thrombin that is already formed or that is produced despite the action of fondaparinux. This agent has been shown to be an effective anticoagulant and is indicated for the treatment of deep venous thrombosis and pulmonary embolism. The OASIS-5 investigators compared a control strategy of enoxaparin 1.0mg/kg SC twice daily (once daily if creatinine clearance was < 30 cc/min), coupled with UFH at the time of PCI if performed more than 6h after the last enoxaparin dose, versus a strategy of fondaparinux 2.5 mg SC daily (one-third the venous thrombosis treatment dose), with more fondaparinux or UFH at the time of PCI. OASIS-5 was designed and powered as a noninferiority trial. After enrollment of about 60% of the 20,078 NSTE- ACS patients in the study, the protocol was amended to allow more UFH in the catheterization laboratory. This was in response to the finding that catheterassociated thrombus was reported three times more frequently (0.9% vs 0.3%) in the fondaparinux arm than in the enoxaparin arm. In OASIS-5, only about two-thirds of the patients underwent diagnostic angiography; just over half of these had PCI and the CABG rate overall was under 10%. The primary ischemic outcome (death, MI, or refractory ischemia) at 9 days showed no difference between the two groups (5.8% with fondaparinux, 5.7% with enoxaparin), but met the noninferiority margin of 18.5%. At 30 days and at 6-month follow-up, patients receiving fondaparinux experienced a nonsignificant trend towards better composite ischemic outcomes, with the two single endpoints of death at 30 days (p = 0.02) and 180 days (p = 0.05), and of stroke at 180 days (p = 0.04) significantly favoring fondaparinux. In the safety analysis of OASIS-5, major bleeding was much less common in the fondaparinux arm at 9 days (2.2% vs 4.1%; hazard ratio 0.52, p < 0.001), driving a net benefit (primary ischemic composite plus major bleeding) that favored fondaparinux (7.3% vs 9.0%; hazard ratio 0.81; 95% CI, 0.73, 0.89; p < 0.001). 5 The 2007 Guidelines recommend fondaparinux at an I-B level, with particular emphasis on choosing it for patients at increased risk for bleeding. 1 Emergency physicians must be aware that patients treated with upstream fondaparinux should receive an additional anticoagulant with antithrombin (specifically, anti-iia) activity at the time of PCI, making it essential that the choice of fondaparinux for initial management be clearly communicated to the interventional team, if applicable. The ACUITY study was more complex than SYNERGY and OASIS-5, involving a subrandomization for antiplatelet therapy as well as a comparison between anticoagulation strategies. 6 The study drug in ACUITY was bivalirudin, a direct (i.e., not requiring Antithrombin III) anti-iia anticoagulant. Bivalirudin is a synthetic analog of hirudin that binds bivalently and reversibly to both circulating and clot-bound thrombin. In ACUITY, bivalirudin with or without Fondaparinux is an indirect (mediated via Antithrombin III, as with UFH and LWMHs) inhibitor of Factor Xa. Bivalirudin is a synthetic analog of hirudin that binds bivalently and reversibly to both circulating and clot-bound thrombin. 3

4 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies The 2007 Guidelines recommend that bivalirudin be used (I-B) in the patient undergoing an early invasive approach, and (IIa-B) that when given with a clopidogrel loading dose at least 6 hours prior to cath, can be used without a GPI. upstream GPI was compared with a heparin (UFH or enoxaparin) with or without upstream GPI, and to bivalirudin with GPI given only provisionally, in 13,819 patients destined for an early invasive approach. The randomization was unblinded and could occur after treatment with a heparin or GPI had already been initiated. The study was designed and powered for noninferiority with a large margin of 25%. The dose of bivalirudin used upstream was 0.1 mg/kg IV bolus. The doses of heparin and enoxaparin were the same as those used in SYNERGY. 6 There was a second randomization for timing of GPI administration in the first two arms defined above, between initiation at the time of randomization (by definition, upstream of cath) and at the time of PCI, if performed. Patients enrolled were at moderate to high risk with NSTE-ACS, and in this manner ACUITY differs from SYNERGY and OASIS-5, which evaluated only high-risk patients. The primary outcome in ACUITY was the composite of ischemic complications (death, MI, unplanned revascularization) and major bleeding (inclusive of, but not limited to, TIMI major criteria), termed net clinical benefit. At 30 days, bivalirudin plus GPI showed similar outcomes to heparin plus GPI. Comparing the latter with bivalirudin monotherapy, bivalirudin resulted in noninferior rates of composite ischemia (7.8% vs 7.3%, p = 0.32, relative risk 1.08; 95% CI, 0.93, 1.42), significantly reduced major bleeding (3.0% vs 5.7%, p < 0.001, relative risk 0.53; 95% CI 0.43, 0.65), and significantly improved net clinical outcome (10.1% vs 11.7%, p = 0.015, relative risk 0.86; 95% CI, 0.77, 0.97). 6 Subgroup analysis revealed that much of the ischemic benefit of the bivalirudin monotherapy arm was lost if patients did not also receive a thienopyridine, such as clopidogrel, before angiography or PCI. This is a consideration if bivalirudin is initiated as an anticoagulant in the ED. It is also important to note that the median time from randomization to cath in ACUITY was only four hours, 6 substantially faster than the presentationto-cath interval in contemporary practice. The 2007 Guidelines recommend that bivalirudin be used (I-B) in the patient undergoing an early invasive approach, and (IIa-B) that when given with a clopidogrel loading dose at least 6 hours prior to cath, can be used without a GPI. 1 Bottom Line. Nowhere is it more clear than with anticoagulant therapy that one size does not fit all. Heparin and enoxaparin (Lovenox ), already in widespread use in the ED for patients with NSTE-ACS across a range of risks, continue to be recommended at the I-A level. New recommendations pertinent to the emergency physician include fondaparinux and bivalirudin, both of which carry the advantage of lower bleeding risk and therefore are pertinent when the ACS patient is female, older, anemic, or has diminished renal function. The former has the disadvantage of requiring an additional agent in the catheterization laboratory. The latter has been studied primarily in the patient who is rapidly transitioned to the catheterization laboratory, may require supplemental antiplatelet therapy (in which case agent cost may become an issue), and trends towards poorer ischemic outcomes. The use of either of these new agents will require close cooperation between the ED, the treating cardiologist, and the catheterization laboratory. Earlier this year, bivalirudin (Angiomax ) received a nonapprovable letter from the FDA for an ACUITY-based label for upstream therapy, therefore it should not be used in the ED. FDA review of a proposed OASIS-5-based label for fondaparinux (Arixtra ) is still pending. 4

5 2007 ACC/AHA GUIDELINES FOR THE MANAGEMENT OF NSTE-ACS: OPTIMAL ANTICOAGULATION AND ANTIPLATELET THERAPY Tables 1 and 2 provide the most recent Guidelines recommen dations for anticoagulation therapy, compared to those issued in the 2002 Guidelines. 8 Antiplatelet Therapy Unlike anticoagulation therapy, there has been a relative paucity of new data on antiplatelet therapy since release of the 2002 Guidelines. There are no new data for the use of aspirin (ASA), which has been considered to be standard of care for many years. There are scant new data on clopidogrel, but a combination of broad clinical experience, its ease of administration, the use of drug-eluting stents, and its linkage to new antithrombotic regimens has resulted in wider recommendations for its use. There has been a clarification of the dose of clopidogrel to be used as an aspirin substitute; the recommended approach is to give a loading dose of 300 mg in the ED for those occasional patients with allergy or hypersensitivity to ASA. 1 This is the FDA-labeled loading dose for clopidogrel in all indications pertinent to the ED, but many emergency physicians will collaborate with interventional cardiologists who often load NSTE-ACS patients with 600 mg prior to PCI. A small trial has shown favorable outcomes with this approach, 9 but it has not been validated in large-scale studies. The entire issue of clopidogrel loading is problematic for the emergency physician, who must be concerned that the ACS patient may require CABG after diagnostic catheterization, and that a recent load of clopidogrel will delay or complicate surgery. This issue once more highlights the need for cross-disciplinary collaboration among emergency physicians, cardiologists, and cardiothoracic surgeons to determine an optimal approach for their institution. In contemporary practice, the rate of near-term (during the index hospitalization) CABG among high-risk NSTE-ACS patients is approximately 12%, 9 and among patients without high-risk features it is much lower, with the rate of truly emergent CABG procedures at only about 1%. 10 It is important that the stakeholders in each facility be aware of their own incidence of CABG in these patients, as its low frequency may support broader upstream use of clopidogrel, accepting the increased risk of bleeding if CABG ensues, in order to improve protection from ischemic events. Table 1. Most Recent ACC/AHA Guidelines Recommendations for Anticoagulation Therapy, Compared to Those Issued in the 2002 Guidelines Medical management: preferred over UFH 5

6 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies For patients undergoing early intervention, there is a new I-A recommendation that patients receive a loading dose of clopidogrel or a smallmolecule GPI, and a new IIa-B recommendation that patients managed with an early invasive strategy should receive both clopidogrel and a GPI. An important change between the 2002 and 2007 Guidelines is a new either/or approach to clopidogrel and GPIs in upstream management of NSTE-ACS. 1 For patients undergoing early intervention, there is a new I-A recommendation that patients receive a loading dose of clopidogrel or a small-molecule GPI, and a new IIa-B recommendation that patients managed with an early invasive strategy should receive both clopidogrel and a GPI. 1 The latter approach is actually more intuitive, given that the two antiplatelet agents have different mechanisms (clopidogrel inhibits platelet activation, while GPIs inhibit aggregation of platelets that are already activated) and sites (ADP vs GP IIb/IIIa receptors) of action, but should be pursued with great caution in patients with untoward bleeding risk or when there is increased likelihood (by whatever measure) of near-term CABG. Should this be the case, the safer approach is to use a small-molecule GPI, the effects of which are short-lived (clopidogrel s action is irreversible) and can be discontinued if CABG is required. The clopidogrel-or-gpi approach is more difficult to support from the emergency medicine perspective, given that patients with symptoms of ACS in the ED can be assumed already to have activated platelets, and GPIs are the only class of drugs that inhibit their aggregation. Furthermore, the two antiplatelet therapies have never been compared directly in a prospective study. The Intracoronary Stenting with Antithrombotic Regimen-REACT-2 trial, 11 illustrates this concept. In this study, 2,022 patients undergoing PCI received ASA, UFH, 600 mg clopidogrel, and either abciximab (12 hour infusion) or placebo. Overall, the patients receiving abciximab experienced a lower rate of death or MI (8.9 vs 11.9%), but the benefit was entirely confined to those patients who had elevated troponin levels (i.e., were at higher risk). Further, there was no difference between the two groups in major bleeding complications. 11 This study, then, supports the addition of a GPI to even high-dose clopidogrel in NSTE- ACS patients who are at high risk. Contemporary registry data from the CRUSADE Initiative confirm the utility of GPI therapy in high-risk NSTE- ACS therapy. 9 They also demonstrate the potential for adverse effects of GPI therapy--bleeding, which is often associated with inappropriately high doses. 12 The small-molecule GPIs are excreted through the kidneys, and doses should be adjusted both for creatinine clearance and actual body weight. When this is done, the likelihood of major bleeding with appropriate dosing in contemporary practice diminishes significantly. 9 Bottom Line. Emergency physicians and cardiologists must address proper patient selection, timing of initiation, dose adjustments, and expected management strategy in reaching an evidence-based, consistent, and riskappropriate multidisciplinary protocol for antiplatelet therapy in NSTE-ACS. Aspirin should be given as soon as possible after (even potential) ACS is recognized. Oral antiplatelet therapy with clopidogrel is simple and offers 6

7 2007 ACC/AHA GUIDELINES FOR THE MANAGEMENT OF NSTE-ACS: OPTIMAL ANTICOAGULATION AND ANTIPLATELET THERAPY ischemic benefit, but is associated with substantially increased bleeding risk if the patient requires near-term CABG that cannot be delayed 5 days, as its effects on platelets are irreversible. Small-molecule GPI therapy is reversible and offers ischemic protection when platelets are already activated, but is also associated with bleeding risk--although this can be minimized with proper dosing based on weight and estimated creatinine clearance. 8 Anticoagulation and antiplatelet therapy are foundational approaches to ACS management that are often appropriate for initiation in the ED. As with all aspects of ACS care, choices among various therapeutic options are best made in an evidence-based, risk-driven fashion according to a prospectively developed protocol that insures consistency across the continuum of care from ED to cath lab to inpatient care. Table 2. Most Recent ACC/AHA Guidelines Recommendations for Antiplatelet Therapy, Compared To Those Issued In the 2002 Guidelines Not appropriate for medical management when PCI not planned < 24h 7

8 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies REFERENCES 1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007;50:e Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114: Haan CK, O Brien S, Edwards FH, et al. Trends in emergency coronary artery bypass grafting after percutaneous coronary intervention, Ann Thorac Surg 2006;81: Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295: Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-st-segment elevation acute coronary syndromes. JAMA 2005;294: Moscucci M, Fox KAA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24: Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-st-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292: Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354: Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355: Mahaffey KW, Ferguson JJ. Exploring the role of enoxaparin in the management of high-risk patients with non-st-elevation acute coronary syndromes: the SYNERGY trial. Am Heart J 2005;149:S81 S Pollack CV, Brauwald E Update to the ACC/AHA Guidelines for the Management of Patients With Unstable Angina and Non ST- Segment Elevation Myocardial Infarction: Implications for Emergency Department Practice. Ann Emerg Med 2008;51: Data available at 8